Individual variations in immune status and function determine responses to infection and contribute to disease severity and outcome. In this proposal, we will employ recent advances in high-throughput technology to profile individual immune responses to identify the molecular signatures defining individual immune responses to flaviviral infections. We will investigate the immune responses of patients from stratified cohorts using as models West Nile virus (WNV), generally a transient infection, and hepatitis C virus (HCV), which can be transient with a resolving viremia, or chronic with a persistent viremia leading to cirrhosis and death. Using highly sensitive multidimensional cell flow cytometry, multiplexed gene expression analysis, and correlation with clinical history, we will provide molecular profiles of cellular mechanisms of primary human immune cells. The profiling studies of Aims 1 and 2 will form the basis for modeling and predictions of networks and critical cellular pathways to identify key effectors and regulatory mechanisms of resistance to flaviviral infections (see Research Project 3). These predictions will be validated through detailed examination in primary cells to demonstrate the role of identified components.